Heritability Of Blood Pressure Research Articles

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Genetic and Epigenetic Mechanisms Regulating Blood Pressure and Kidney Dysfunction.

The pioneering work of Dr Lewis K. Dahl established a relationship between kidney, salt, and high blood pressure (BP), which led to the major genetic-based experimental model of hypertension. BP, a heritable quantitative trait affected by numerous biological and environmental stimuli, is a major cause of morbidity and mortality worldwide and is considered to be a primary modifiable factor in renal, cardiovascular, and cerebrovascular diseases. Genome-wide association studies have identified monogenic and polygenic variants affecting BP in humans. Single nucleotide polymorphisms identified in genome-wide association studies have quantified the heritability of BP and the effect of genetics on hypertensive phenotype. Changes in the transcriptional program of genes may represent consequential determinants of BP, so understanding the mechanisms of the disease process has become a priority in the field. At the molecular level, the onset of hypertension is associated with reprogramming of gene expression influenced by epigenomics. This review highlights the specific genetic variants, mutations, and epigenetic factors associated with high BP and how these mechanisms affect the regulation of hypertension and kidney dysfunction.

Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure

Genome-wide association studies (GWASs) have identified numerous variants associated with polygenic traits and diseases. However, with few exceptions, a mechanistic understanding of which variants affect which genes in which tissues to modulate trait variation is lacking. Here, we present genomic analyses to explain trait heritability of blood pressure (BP) through the genetics of transcriptional regulation using GWASs, multiomics data from different tissues, and machine learning approaches. Approximately 500,000 predicted regulatory variants across four tissues explain 33.4% of variant heritability: 2.5%, 5.3%, 7.7%, and 11.8% for kidney-, adrenal-, heart-, and artery-specific variants, respectively. Variation in the enhancers involved shows greater tissue specificity than in the genes they regulate, suggesting that gene regulatory networks perturbed by enhancer variants in a tissue relevant to a phenotype are the major source of interindividual variation in BP. Thus, our study provides an approach to scan human tissue and cell types for their physiological contribution to any trait.

Abstract 135: The Noncoding Haplotype Region Of Blood Pressure-associated Single Nucleotide Polymorphism Rs1173771 Regulates The Expression Of Natriuretic Peptide Receptor C

Genome-wide association studies have identified 1,071 loci containing 26,585 single nucleotide polymorphisms (SNPs) as associated with blood pressure (BP). These loci together explain more than 25% of BP heritability. The BP-associated SNP rs1173771 has been associated with NPR3 expression in human tissues. NPR3 encodes natriuretic peptide receptor C (NPR-C). The haplotype in linkage disequilibrium (LD) with rs1173771 contains 11 SNPs spanning a noncoding genomic region of more than 17 kbp. The haplotype region is located 126 kbp from the transcription start site of NPR3 . We used genome editing to examine the effect of the noncoding haplotype region in LD with rs1173771 on gene expression. We employed a CRISPR/Cas9 mediated genetic engineering approach to delete the 17 kbp haplotype region in a human induced pluripotent stem cell (iPSC) line. Two clones of iPSCs with homozygous deletion of the 17 kbp region were obtained after screening 50 single cell clones. The genomic modification was confirmed by PCR, Sanger sequencing, and whole genome sequencing. Immunofluorescence staining for pluripotency markers indicated that pluripotency was retained following the genome editing procedures. Each edited iPSC clone and the unedited iPSC line were differentiated into endothelial cells (iECs) in 3 independent rounds of differentiation. Real-time PCR analysis showed a 1.59±0.17-fold upregulation of NPR3 mRNA in iECs with the haplotype region deletion compared to unedited iECs (n=11 and 7, p&lt;0.05). The expression of other neighboring genes ( SUB1 and TARS ) and a distal gene ( MRPS30 ) was not significantly affected by the deletion. The results provide definitive evidence that the noncoding haplotype region in LD with BP-associated SNP rs1173771 regulates the expression of natriuretic peptide receptor C in iECs.

Genetic and Environmental Influences on Blood Pressure and Serum Lipids Across Age-Groups.

Aging plays a crucial role in the mechanisms of the impacts of genetic and environmental factors on blood pressure and serum lipids. However, to our knowledge, how the influence of genetic and environmental factors on the correlation between blood pressure and serum lipids changes with age remains to be determined. In this study, data from the Chinese National Twin Registry (CNTR) were used. Resting blood pressure, including systolic and diastolic blood pressure (SBP and DBP), and fasting serum lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) were measured in 2378 participants (1189 twin pairs). Univariate and bivariate structural equation models examined the genetic and environmental influences on blood pressure and serum lipids among three age groups. All phenotypes showed moderate to high heritability (0.37-0.59) and moderate unique environmental variance (0.30-0.44). The heritability of all phenotypes showed a decreasing trend with age. Among all phenotypes, SBP and DBP showed a significant monotonic decreasing trend. For phenotype-phenotype pairs, the phenotypic correlation (Rph) of each pair ranged from -0.04 to 0.23, and the additive genetic correlation (Ra) ranged from 0.00 to 0.36. For TC&SBP, TC&DBP, TG&SBP and TGs&DBP, both the Rph and Ra declined with age, and the Ra difference between the young group and the older adult group is statistically significant (p < .05). The unique environmental correlation (Re) of each pair did not follow any pattern with age and remained relatively stable with age. In summary, we observed that the heritability of blood pressure was affected by age. Moreover, blood pressure and serum lipids shared common genetic backgrounds, and age had an impact on the phenotypic correlation and genetic correlations.

Shared Heritability of Blood Pressure and Pulse Wave Velocity: Insights From the STANISLAS Cohort.

Pulse wave velocity (PWV) is a marker of arterial stiffness, which is intrinsically highly correlated with blood pressure (BP). However, the interplay of PWV and BP heritability has not been extensively studied. This study aimed to estimate the heritability of PWV and BP and determine the genetic correlation between PWV and BP. The heritability of PWV and BP was estimated in 1080 subjects from the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort with at least one relative using a linear mixed model within one frequentist and one Bayesian framework implemented, respectively, in the Gaston and MCMCglmm R packages. Then their genetic correlations were also estimated. The heritability estimations for PWV were within the same range of the heritability of systolic BP and diastolic BP (23%, 19%, and 27%, respectively). Daytime heritability of BP was higher than nighttime BP. In addition, phenotypic correlations between PWV and systolic BP/diastolic BP were, respectively, 0.34 and 0.23, whereas nonsignificant genetic correlations were 0.08 and 0.22 respectively, indicating that PWV and diastolic BP shared more polygenic codeterminants than PWV and systolic BP. Our results suggest that the heritability of PWV is >20% and within the same range as BP heritability. It also suggests that the link between PWV and BP goes beyond phenotypic association: PWV and BP (in particular diastolic BP) share common genetic determinants. This genetic interdependence of PWV and BP appears largely polygenic.

Mitochondrial tRNALeu(UUR) Mutations in Patients with Essential Hypertension

Arterial hypertension remains a major modifiable risk factor for cardiovascular disease. Previous studies have noted a maternal effect on blood pressure (BP). Mutations in mitochondrial DNA (mtDNA) have become an additional target of investigations on the missing BP heritability. The major objective of the present work was to investigate mutations in the tRNALeu(UUR) gene in 20 Pakistani patients with EH and compare the amplified sequences to the mitochondrial reference sequence. DNA was extracted from their saliva, and the mitochondrial tRNALeu(UUR) gene was amplified using PCR with specified primers. The present study did not find mutations in the tRNALeu(UUR) gene in Pakistani EH patients. Further studies are needed for confirmation.

Are cardiovascular health measures heritable across three generations of families in Soweto, South Africa? A cross-sectional analysis using the random family method

ObjectivesCardiovascular disease is increasing in many low and middle-income countries, including those in Africa. To inform strategies for the prevention of cardiovascular disease in South Africa, we sought to determine...

DNA Methylation and Blood Pressure Phenotypes: A Review of the Literature.

Genetic studies of DNA have been unable to explain a significant portion of the variance of the estimated heritability of blood pressure (BP). Epigenetic mechanisms, particularly DNA methylation, have helped explain additional biological processes linked to BP phenotypes and diseases. Candidate gene methylation studies and genome-wide methylation studies of BP have highlighted impactful cytosine-phosphate-guanine (CpG) markers across different ethnicities. Furthermore, many of these BP-related CpG sites are also linked to metabolism-related phenotypes. Integrating epigenome-wide association study data with other layers of molecular data such as genotype data (from single nucleotide polymorphism arrays or sequencing), other epigenetic data, and/or transcriptome data can provide additional information about the significance and complexity of these relationships. Recent data suggest that epigenetic changes can be consequences rather than causes of BP variation. Finally, these data can give insight into downstream effects of long-standing high BP (due to target organ damage (TOD)). The current review provides a literature overview of epigenetic modifications in BP and TOD. Recent studies strongly support the importance of epigenetic modifications, such as DNA methylation, in BP and TOD for relevant biological insights, reliable biomarkers, and possible future therapeutics.

Genomics of hypertension: the road to precision medicine.

The known genetic architecture of blood pressure now comprises >30 genes, with rare variants resulting in monogenic forms of hypertension or hypotension and >1,477 common single-nucleotide polymorphisms (SNPs) being associated with the blood pressure phenotype. Monogenic blood pressure syndromes predominantly involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, with a smaller fraction caused by neuroendocrine tumours of the sympathetic and parasympathetic nervous systems. The SNPs identified in genome-wide association studies (GWAS) as being associated with the blood pressure phenotype explain only approximately 27% of the 30-50% estimated heritability of blood pressure, and the effect of each SNP on the blood pressure phenotype is small. A paucity of SNPs from GWAS are mapped to known genes causing monogenic blood pressure syndromes. For example, a GWAS signal mapped to the gene encoding uromodulin has been shown to affect blood pressure by influencing sodium homeostasis, and the effects of another GWAS signal were mediated by endothelin. However, the majority of blood pressure-associated SNPs show pleiotropic associations. Unravelling these associations can potentially help us to understand the underlying biological pathways. In this Review, we appraise the current knowledge of blood pressure genomics, explore the causal pathways for hypertension identified in Mendelian randomization studies and highlight the opportunities for drug repurposing and pharmacogenomics for the treatment ofhypertension.

Genetic and Environmental Influences on Blood Pressure and Body Mass Index in the National Academy of Sciences-National Research Council World War II Veteran Twin Registry.

Blood pressure (BP) and obesity phenotypes may covary due to shared genetic or environmental factors or both. Furthermore, it is possible that the heritability of BP differs according to obesity status-a form of G×E interaction. This hypothesis has never been tested in White twins. The present study included 15 924 White male twin pairs aged between 15 and 33 years from the National Academy of Sciences-National Research Council World War II Veteran Twin Registry. Systolic and diastolic BPs, as well as height and weight, were measured at the induction physical examination. Body mass index (BMI) was used as the index of general obesity. Quantitative genetic modeling was performed using Mx software. Univariate analysis showed that narrow sense heritabilities (95% CI) for systolic BP, diastolic BP, height, and BMI were 0.401 (0.381-0.420), 0.297 (0.280-0.320), 0.866 (0.836-0.897), and 0.639 (0.614-0.664), respectively. Positive phenotypic correlations of BMI with systolic BP (r=0.13) and diastolic BP (r=0.08) were largely due to genetic factors (70% and 86%, respectively). The gene-BMI interaction analysis did not show any support for a modifying effect of BMI on genetic and environmental influences of systolic BP and diastolic BP. Our results suggest that correlations between BP and BMI are mainly explained by common genes influencing both. Higher BMI levels have no influence on the penetrance of genetic vulnerability to elevated BP. These conclusions may prove valuable for gene-finding studies.

Haploinsufficiency of ARHGAP42 is associated with hypertension.

Family studies have established that the heritability of blood pressure is significant and genome-wide association studies (GWAS) have identified numerous susceptibility loci, including one within the non-coding part of Rho GTPase-activating protein 42 gene (ARHGAP42) on chromosome 11q22.1. Arhgap42-deficient mice have significantly elevated blood pressure, but the phenotypic effects of human variants in the coding part of the gene are unknown. In a Danish cohort of carriers with apparently balanced chromosomal rearrangements, we identified a family where a reciprocal translocation t(11;18)(q22.1;q12.2) segregated with hypertension and obesity. Clinical re-examination revealed that four carriers (age 50-77 years) have had hypertension for several years along with an increased body mass index (34-43 kg/m2). A younger carrier (age 23 years) had normal blood pressure and body mass index. Mapping of the chromosomal breakpoints with mate-pair and Sanger sequencing revealed truncation of ARHGAP42. A decreased expression level of ARHGAP42 mRNA in the blood was found in the translocation carriers relative to controls and allele-specific expression analysis showed monoallelic expression in the translocation carriers, confirming that the truncated allele of ARHGAP42 was not expressed. These findings support that haploinsufficiency of ARHGAP42 leads to an age-dependent hypertension. The other breakpoint truncated a regulatory domain of the CUGBP Elav-like family member 4 (CELF4) gene on chromosome 18q12.2 that harbours several GWAS signals for obesity. We thereby provide additional support for an obesity locus in the CELF4 domain.

Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation.

Blood pressure (BP) is a highly heritable trait and a major cardiovascular disease risk factor. Genome wide association studies (GWAS) have implicated a number of susceptibility loci for systolic (SBP) and diastolic (DBP) blood pressure. However, a large portion of the heritability cannot be explained by the top GWAS loci and a comprehensive understanding of the underlying molecular mechanisms is still lacking. Here, we utilized an integrative genomics approach that leveraged multiple genetic and genomic datasets including (a) GWAS for SBP and DBP from the International Consortium for Blood Pressure (ICBP), (b) expression quantitative trait loci (eQTLs) from genetics of gene expression studies of human tissues related to BP, (c) knowledge-driven biological pathways, and (d) data-driven tissue-specific regulatory gene networks. Integration of these multidimensional datasets revealed tens of pathways and gene subnetworks in vascular tissues, liver, adipose, blood, and brain functionally associated with DBP and SBP. Diverse processes such as platelet production, insulin secretion/signaling, protein catabolism, cell adhesion and junction, immune and inflammation, and cardiac/smooth muscle contraction, were shared between DBP and SBP. Furthermore, “Wnt signaling” and “mammalian target of rapamycin (mTOR) signaling” pathways were found to be unique to SBP, while “cytokine network”, and “tryptophan catabolism” to DBP. Incorporation of gene regulatory networks in our analysis informed on key regulator genes that orchestrate tissue-specific subnetworks of genes whose variants together explain ~20% of BP heritability. Our results shed light on the complex mechanisms underlying BP regulation and highlight potential novel targets and pathways for hypertension and cardiovascular diseases.

Heritability of Blood Pressure Among Random Adult Individuals of South Indian States

Heritability of Blood Pressure Among Random Adult Individuals of South Indian States

Advances in the Genetics of Hypertension: The Effect of Rare Variants.

Worldwide, hypertension still represents a serious health burden with nine million people dying as a consequence of hypertension-related complications. Essential hypertension is a complex trait supported by multifactorial genetic inheritance together with environmental factors. The heritability of blood pressure (BP) is estimated to be 30–50%. A great effort was made to find genetic variants affecting BP levels through Genome-Wide Association Studies (GWAS). This approach relies on the “common disease–common variant” hypothesis and led to the identification of multiple genetic variants which explain, in aggregate, only 2–3% of the genetic variance of hypertension. Part of the missing genetic information could be caused by variants too rare to be detected by GWAS. The use of exome chips and Next-Generation Sequencing facilitated the discovery of causative variants. Here, we report the advances in the detection of novel rare variants, genes, and/or pathways through the most promising approaches, and the recent statistical tests that have emerged to handle rare variants. We also discuss the need to further support rare novel variants with replication studies within larger consortia and with deeper functional studies to better understand how new genes might improve patient care and the stratification of the response to antihypertensive treatments.

Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin-Angiotensin-Aldosterone System and Blood Pressure.

Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis). We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at ACE and rs12721297 at AGTR1) were individually associated with lower systolic blood pressure with significant (P<0.00076) effect sizes ≈1.7 to 2.5 mm Hg. Sex-specific associations were seen for 3 SNPs in men (rs2468523 and rs2478544 at AGT and rs11658531 at ACE) and 1 SNP in women (rs12451328 at ACE). SNP-SNP interaction was suggested (P<0.005) for 14 SNP pairs, none of which had shown individual association with systolic blood pressure. Four SNP pairs were at the same gene (2 for REN, 1 for AGT, and 1 for AGTR1). The SNP rs3097 at CYP11B2 was represented in 5 separate pairs. SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype.

The relationship between the nitric oxide synthase gene and the risk of hypertension defi ned according to ambulatory blood pressures

Although nitric oxide (NO) plays an important role in blood pressure (BP) control, whether variation of genes involved in regulating the synthesis of NO infl uences BP is uncertain. As the heritability of BP is stronger for ambulatory than it is for conventional BP, we assessed the independent association of the well described functional exon 7 Glu298Asp variant of the eNOS gene with the presence of hypertension in 511 randomly selected normotensive control participants and 503 hypertensives with a diagnosis of hypertension confi rmed with 24-hour ambulatory BP profiles whilst off therapy. We also assessed the relationship between eNOS genotype and 24 hour ambulatory BP. Comparisons of genotype and allele frequencies indicated a lack of association of the exon 7 Glu298Asp gene variant with hypertension (Odds ratio of genotype predicting the presence of hypertension=0.97, confidence interval=0.70-1.30, p=0.92). However, patients with the Glu/Glu genotype of the Glu298Asp variant (n=424) had increased 24-hour systolic and diastolic blood pressures (152±1/97±1 mm Hg) in comparison to patients heterozygous for the Glu298Asp variant or homozygous for the 298Asp allele (n=79) (145±1/94±1 mm Hg, p‹0.005 for systolic BP and p‹0.001 for diastolic BP after multiple adjustments including age, gender, body mass index and the presence of diabetes mellitus). Differences in systolic and diastolic BP between genotype groups were noted during the day as well as at night. The association of eNOS genotype with ambulatory BP translated into an increased risk of more severe grades of hypertension in patients with the Glu/Glu genotype (grade II and III vs. grade I, Odds ratio=2.20, confidence interval=1.34-3.59, p‹0.0002). In conclusion, a functional gene variant (Glu298Asp) at the eNOS locus contributes ~1.4-2.5% to the variation in ambulatory blood pressure within hypertensives, but is not associated with the presence of hypertension in patients in whom the diagnosis has been confirmed by 24-hour ambulatory BP values. The relationship between eNOS genotype and 24-hour ambulatory BP and the severity of hypertension warrants further study.

A Novel CRISPR/Cas9 Knock‐in Rat Model Defines A Polymorphic Variant of Secreted Phosphoprotein 2 as A Quantitative Trait Nucleotide Linked to The Heritability of Blood Pressure

Hypertension is a complex polygenic disease caused by a combination of inherited (genetic) and environmental factors. Rat models of inherited hypertension serve as tools to dissect and prioritize genetic factors as candidate genes causing hypertension. One such candidate gene prioritized through systematic linkage and substitution mapping is Spp2 or Secreted Phosphoprotein 2. A single non‐synonymous G/T polymorphism between the Dahl Salt‐ Sensitive (S) rats and Spontaneously Hypertensive Rats (SHR) at the Spp2 locus was hypothesized to cause a reduction in blood pressure (BP) observed in the S.SHR congenic strain spanning the Spp2 locus. To test this hypothesis, a novel rat model was generated using the CRISPR/Cas9 precision‐engineering technology, whereby the ‘G’ allele at the Spp2 locus of the S rat was replaced by the ‘T’ allele of the SHR rat. Protein modeling prediction by SWISSPROT indicated a significantly altered protein structure of the Spp2 protein in the resultant Spp2 knock‐ in rescue model. Following transgenesis, pups born were genotyped and grouped into founders and non‐founders. The founder and non‐founder rats were isogenic except for the Spp2 locus, wherein the founder S rats contained the ‘G’ allele and the non‐founder S rats contained the ‘T’ allele. Both founder and non‐founder rats (n=12 male rats/group) were fed a high salt (2% NaCl) containing diet and their BP was monitored by radiotelemetry. Both systolic and diastolic BP of the Spp2 knock‐in rescue model were significantly lower compared to that of the non‐founder S rats. These data provide conclusive evidence for a single nucleotide polymorphism within the Spp2 gene as a quantitative trait nucleotide (QTN) responsible for the inheritance of blood pressureSupport or Funding InformationFunding for this work to BJ from the NHLBI/NIH (HL020176) is gratefully acknowledged

PP.23.11] MATRIX METALLOPROTEINASE 2 GENE POLYMORPHISM ASSOCIATES WITH RESISTANT HYPERTENSION

Objective: The lack of blood pressure (BP) control (>140/90 mmHg) – even in the presence of three or more antihypertensive drugs of different classes - define the hypertensive patients at high cardiovascular (CV) risk and high incidence of target organ damage (TOD) as resistant hypertensives (RH). Studies suggest the involvement of metalloproteinase 2 (MMP-2) in hypertension and in CV remodeling associated with TOD. Hypertension is a multifactorial condition in which BP heritability and genetic factors may have a large contribution in the development of the disease. MMP-2 single nucleotide polymorphisms (SNPs) have been associated with the predisposition of CV alterations. Few studies have evaluated the impact of MMP-2 polymorphisms on clinical conditions and their influence in RH is unknown. The aim of this study is to analyze the influence of MMP-2 SNPs in RH, as well as their association with TOD in this high CV risk group. Design and method: 119 RH patients and 136 mild to moderate hypertensives (HT) were included and submitted to clinical and laboratorial evaluations. We assessed genotypes by allelic discrimination assay using real time polymerase chain reaction. We compare clinical and laboratorial characteristics according to SNPs genotypes/haplotypes (rs243865, rs243866 and rs2285053). TOD were categorized by left ventricular mass index (women >95 g/m2 and men >115 g/m2) and arterial stiffness (PWV>10m/s). Results: We did not find association of studied SNPs with TOD and clinical features. However, the allelic and genotype frequencies of rs2285053 showed to be different between RH and HT subjects (C vs T, p = 0.02; CC vs CT vs TT, p = 0.04, respectively), with high prevalence of C allele in the RH group. Moreover, haplotype frequencies were also different (GCC vs GCT vs ATC, p = 0.03) between groups. Finally, regression analysis demonstrated that haplotype was associated with resistance to treatment, as well as age, gender, race, BMI, LVH and aldosterone levels. Conclusions: We conclude that only the SNP rs2285053 may be associated with RH when compared to controlled counterparts. Our finding suggests that the presence of C allele may have some bearing in the resistance to antihypertensive process.

Abstract 32: Novel Genetic Loci for Blood Pressure Regulation Identified by the Analysis of DNA Methylation

Both the health burden and genetic heritability of blood pressure are well-established, yet only a fraction of blood pressure genes have been identified. Epigenetic changes in or near genes related to blood pressure may explain part of its variance and provide new insights into the biological mechanisms involved in blood pressure regulation. DNA methylation measured on the Infinium HumanMethylation450 BeadChip was tested for association with systolic and diastolic blood pressure in individuals of European (EA) and African ancestry (AA) in the ARIC, CHS, FHS, GENOA, GOLDN, NAS, LBC1936, RS-III, and TwinsUK cohorts (N-total=9,828; N-EA=6,650, N-AA=3,178). In each cohort, linear mixed models were used to estimate associations adjusting for age, sex, blood cell counts, BMI, smoking, and ancestry, as well as surrogate variables and technical covariates to control for batch effects. Effect estimates from all cohorts were combined using inverse variance fixed effects meta-analysis; heterogeneity of effects in race- and sex-stratified analyses was not observed. Thirty-one methylation probes were found to be significantly associated with blood pressure after Bonferroni correction (p&lt;1E-7) and eight of these probes replicated with p &lt;0.05 in meta-analyses of EA, AA, and Hispanic/Latino individuals in the MESA cohort (N-total=1,183). Replicated probes tended to be enriched for location in gene enhancer regions and DNase I hypersensitivity sites. ENCODE annotation of these probes revealed two probes to be in enhancer regions for genes involved in angiogenesis, vasoconstriction/vasodilation, and the renin-angiotensin system, including SRF and VEGFA (cg18120259) and PTPN6 and SCNN1A (cg10601624). Additionally, SNPs in these probe-enhanced genes have not been reported to associate with blood pressure or hypertension in prior genetic studies of EA or AA populations, suggesting a novel epigenetic determinant of these traits. Additional replicated probes are located in PHGDH (cg14476101), TXNIP (cg19693031), SLC7A11 (cg06690548), and ZMIZ1 (cg00533891). Previous associations of these probes have been reported with BMI (PHGDH cg14476101); type II diabetes and related traits (TXNIP cg19693031); and IgE and A-diol levels (SLC7A11 cg06690548). SNPs in TXNIP have previously shown associations with blood pressure-related phenotypes, including type II diabetes, and the TXNIP protein has a biological role in the function of calcium channel blockers used to treat hypertension. The association of TXNIP with systolic blood pressure is also supported by gene expression results in FHS. Narrow-sense heritability of the eight replicated probes ranged from 30-65% in whole blood samples from FHS family data, whereas epigenome-wide heritability averaged 12%. Our findings suggest a novel genetic regulation of known blood pressure systems through heritable DNA methylation.